In the current field of pharmaceutical development, tests to determine beneficial effects and safety studies are conducted using non-human animals such as mice, rats, dogs, or monkeys in order to select candidate drugs from many chemical substances. Clinical trials are performed for candidate drugs, the effectiveness and safety of which have been confirmed by such studies and tests using these animals. However, it is known that animals and humans differ significantly in their capacity to metabolize chemical substances and drugs. Accordingly, even in the case of a candidate drug, the effectiveness and safety of which have been confirmed by animal studies, no beneficial effect may be observed, or toxicity may occur in clinical trials. This is a major issue in the pharmaceutical development field.
Various enzymes that catalyze oxidation, reduction, or the like are involved in the in vivo metabolism of chemical substances. One of the most important enzymes is an oxidase referred to as cytochrome P450 (hereinafter, referred to as “CYP” or “Cyp”). CYP is mainly present in the liver, playing an important role in the in vivo metabolism of chemical substances and drugs in humans and animals.
Various types of CYP have been confirmed to date, and they are classified into families and then into subfamilies based on the homology of their amino acid sequences (Non-patent Literature 1).
CYPs exhibit different properties in humans and animals, even if they belong to the same subfamily. Specifically, differences have been confirmed in the substances to be used as substrates and metabolites. Therefore, it is considered that information obtained with the use of animals concerning the metabolism of a chemical substance or a drug cannot be directly applied to humans.
Because of this problem, the U.S. Food and Drug Administration recommends that in vitro tests be conducted using cultured human hepatocytes in preclinical trials. However, cultured hepatocytes do not have functions equivalent to those of the liver in vivo, and thus the precise prediction of human in vivo metabolism of chemical substances or drugs based on an in vitro test system is difficult.
Consequently, in vivo test systems prepared by transplanting human hepatocytes into animals have been developed (Patent Literature 1, Non-patent Literature 2-6). However, such in vivo test systems are problematic since the livers of host animals cannot be completely substituted with transplanted human hepatocytes. As a result, the metabolism of a given drug can still be affected by remaining host hepatocytes. Therefore, such in vivo test systems are insufficient as animal models for the precise evaluation of the capacity of human hepatocytes to metabolize chemical substances and drugs.
Hence, the development of a new test system that reflects the human metabolic system for drugs and chemical substances is still desirable in the art.